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Targeting Acinetobacter baumannii wound infections: From transcriptional profiling to drug repurposing and bioactive hydrogel development

2026-10-14T08:40:09Z

Title: Targeting Acinetobacter baumannii wound infections: From transcriptional profiling to drug repurposing and bioactive hydrogel development Authors: Han, Jie Abstract: Antimicrobial resistance (AMR) is an increasing public health emergency, driven largely by the overuse and misuse of antibiotics. Among multidrug-resistant pathogens, Acinetobacter baumannii is a major clinical concern due to its ability to survive in hospital environments. Recent studies have shown that artificial sweeteners, including acesulfame potassium (Ace-K), sodium saccharin (SACC), and sodium cyclamate (CYC), can inhibit bacterial growth, motility, and biofilm formation, and may enhance antibiotic activity in vitro. However, effective delivery of these compounds to wound infection sites remains a significant challenge. This thesis investigates alternative non-antibiotic strategies for targeting A. baumannii, with a focus on artificial sweetener-loaded polyvinyl alcohol (PVA)-based hydrogels, behaviour changing in wound-mimic environment, 3D-printable hydrogel development, and screening of FDA-approved drugs that modulate virulence-associated pathways. PVA-Borax and freezethaw PVA hydrogels were formulated with Ace-K, SACC, and CYC and demonstrate strong antimicrobial activity. In addition, this thesis explores how A. baumannii behaves in a woundmimic environment in Lubbock chronic wound biofilm (LCWB) medium. Under LCWB conditions, it induced reduced biofilm formation and iron-starvation responses. With iron supplementation, biofilm formation was restored. This highlights that iron is limited in the LCWB medium and is an important regulator of A. baumannii behaviour. Moreover, a 3Dprintable PVA/hydroxypropyl methylcellulose (HPMC) hydrogel was then developed to improve mechanical properties and control antimicrobial release. The optimised PVA/HPMC/SACC formulation demonstrated improved printability, structural integrity, swelling behaviour, rapid SACC release and antimicrobial activity compared with non-printed formulations. Finally, a high-throughput screen of an FDA-approved drug library identified compounds that regulate pilA expression and biofilm formation in A. baumannii. A cancer drug pomalidomide, was identified as a key hit that suppressed pilA expression, reduced twitching-associated behaviour, enhanced biofilm formation, and increased infection severity in Galleria mellonella and murine infection models. Overall, these findings demonstrate that effective control of A. baumannii wound infections requires more than identifying antimicrobial compounds alone. It also requires wound-relevant testing models, rational biomaterial-based delivery systems, and careful evaluation of how nonantibiotic compounds influence bacterial physiology and virulence. Description: This thesis was submitted for the award of Doctor of Philosophy and was awarded by Brunel University London

Severe obesity as an oligogenic condition: evidence from 1714 adults seeking treatment in the UK National Health Service

2026-09-09T02:08:40Z

Title: Severe obesity as an oligogenic condition: evidence from 1714 adults seeking treatment in the UK National Health Service Authors: Almansoori, Sumaya; Amin, Hasnat A; Alsters, Suzanne I; Handley, Dale; Yiorkas, Andrianos M; Hashim, Nikman Adli Nor; Ramzi, Nurul Hanis; Bonanomi, Gianluca; Small, Peter; Purkayastha, Sanjay; van Haelst, Mieke; Walters, Robin G; le Roux, Carel W; Chahal, Harvinder S; Drenos, Fotios; Blakemore, Alexandra IF Abstract: Previous evidence has established genetics as an important contributing factor to severe (class III) obesity, which is a chronic, relapsing condition, with a high burden of comorbidity and mortality. We therefore designed a custom genotyping array to screen a cohort of UK patients seeking treatment for severe obesity in a cost-effective way. A total of 1,714 participants were genotyped using a custom AXIOM array, focusing on rare (minor allele frequency < 0.01) variants, with CADD-PHRED ≥ 15 in 78 genes known/suspected to cause Mendelian forms of obesity. Concordance analyses of 22 duplicate samples and 66 samples with whole exome sequence data revealed good genotyping reliability. We identified the proportion of study participants who carried, or were homozygous for, rare, predicted-deleterious variants in genes with dominant and recessive modes of inheritance (MOI), respectively. 27% of patients carried relevant mutations consistent with the expected MOI, which was very similar to the rate observed in the UKB 50 K whole exome sequencing dataset. However, the clinical obesity cohort was more likely to carry two or more such variants, in separate genes, than UK Biobank participants (17.1% vs. 13%, p = 0 0.018), which strongly indicates the possibility of oligogenic inheritance. In conclusion, our results provide evidence: that (i) custom genotyping arrays, used with improved algorithms can allow reliable, cost-effective screening for rare genetic variants; (ii) rare mutations in “obesity genes” may be at high prevalence among bariatric patients, as well as in the general population; and (iii) that severe obesity may have an oligogenic pattern of inheritance in some cases. Description: Data availability: Data is provided within the manuscript or supplementary information files. Also additional data supporting the finding of this study are available upon request from the corresponding author.; Supplementary Information is available online at: https://link.springer.com/article/10.1186/s40246-025-00895-7#Sec20 .

Rapid and long-lasting remodelling of the blood transcriptome following bariatric surgery

2026-09-09T02:08:37Z

Title: Rapid and long-lasting remodelling of the blood transcriptome following bariatric surgery Authors: Roux, Julien; Seyres, Denis; Buxton, Jessica L; Handley, Dale; Hofer, Giulia; Alsters, Suzanne I; Herzig, Karl-Heinz; Järvelin, Marjo-Riitta; Blakemore, Alexandra I; Cavelti-Weder, Claudia Abstract: Background/Objectives: Bariatric (or metabolic) surgery is the most effective treatment for severe obesity, resulting in sustained weight loss and rapid improvement in metabolic outcomes. However, it is currently unknown what molecular changes are induced by the surgery, how they relate to the health improvements, how early they occur, and whether they are maintained over time. Subjects/Methods: In this study, we characterised early gene expression changes following surgery in blood samples from the ‘Personalised Medicine for Morbid Obesity’ cohort. Results: We observed widespread changes in gene expression only a few days after surgery. Pathways related to immune response were affected, in particular with a decreased expression of the NF-κB pathway and neutrophil cytotoxic activity genes, suggesting a reduction of the inflammatory state typically associated with obesity. Metabolic signalling was also affected, with decreased expression of genes from pathways related to glucagon and insulin secretion, and key regulators such as the appetite-controlling hormone ghrelin. Comparisons to publicly available transcriptomics datasets showed that beyond these specific changes, bariatric surgery induces a transcriptome-wide reversal of expression changes associated with obesity and with forms of type 2 diabetes related to obesity. Comparisons to transcriptomics studies with longer-term follow-ups after bariatric surgery showed that a large fraction of early-induced expression changes likely persist for several months. Conclusions: Taken together, we show that previously unreported early changes in blood gene expression after bariatric surgery provide in-depth insights into the resolution of the chronic inflammation associated with severe obesity and its connection with metabolic improvement. Description: Data availability: Processed data (read count table) are available from GEO, under accession GSE273902. Raw data are not available due to patient privacy concerns.

Disruption of the thyroid hormone system and patterns of altered thyroid hormone serum concentrations after chemical exposures in adult rodents – a systematic review

2026-09-28T09:36:38Z

Title: Disruption of the thyroid hormone system and patterns of altered thyroid hormone serum concentrations after chemical exposures in adult rodents – a systematic review Authors: Baig, Asma H; Forner-Piquer, Isabel; Ermler, Sibylle; Kortenkamp, Andreas Abstract: Identification of thyroid hormone system-disrupting chemicals (THSDC) requires a solid understanding of the mechanisms by which exposure leads to adverse outcomes in the thyroid hormone system (THS). In this systematic review we present the results from our extensive evidence mapping of thyroid hormone (TH) and thyroid stimulating hormone (TSH) patterns in serum or plasma, after exposure to various THSDCs in adult rodents. Our review of 234 peer-reviewed studies revealed that only a small group of compounds induced changes in T4 and TSH consistent with the canonical view of the hypothalamic-pituitary-thyroid (HPT) negative feedback loop, whilst the most frequent pattern was a decrease in T4 without TSH changes. The lack of a TSH response may have been due to T4 decreases not being sufficient to change HPT feedback. However, risk-of-bias analysis also identified deficits in TH/TSH analytical methodology, including the timepoints of TH measurements, possibly explaining discrepancies between studies. We further compared T4/TSH patterns to mechanism-of-action information and other THS-related outcomes and found that THSDC frequently affected TH synthesis, induced hepatic enzymes involved in TH metabolism, and exhibited other differences in pharmacokinetic properties. Given the diverse chemical nature of the various THSDCs and variety of molecular targets in the THS, there is likely no single explanation for the different patterns observed. Our compilation of T4/TSH patterns observed after different chemical exposures demonstrated that it is important to not solely rely on the canonical serum hormonal patterns to determine adversity of chemical exposures. Chemicals with different responses should be carefully considered, as current regulatory criteria may fail to identify them as being harmful to human health. Description: Data availability statement: The original contributions presented in the study are included in the article/Supplementary Material. Further inquiries can be directed to the corresponding author.; Supplementary material: The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fendo.2026.1911254/full#supplementary-material